Novel inhibitors of HSV-1 protease effective in vitro and in vivo

Magdalena Pachota; Renata Grzywa; Jakub Iwanejko; Aleksandra Synowiec; Dominika Iwan; Karolina Kamińska; Marcin Skoreński; Ewa Bielecka; Krzysztof Szczubiałka; Maria Nowakowska; Cameron D Mackereth; Elżbieta Wojaczyńska; Marcin Sieńczyk; Krzysztof Pyrć

doi:10.1016/j.antiviral.2023.105604

Novel inhibitors of HSV-1 protease effective in vitro and in vivo

Antiviral Res. 2023 May:213:105604. doi: 10.1016/j.antiviral.2023.105604. Epub 2023 Apr 11.

Authors

Affiliations

¹ Virogenetics Laboratory of Virology, Małopolska Centre of Biotechnology, Jagiellonian University, Gronostajowa 7a, 30-387, Kraków, Poland; Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387, Kraków, Poland.
² Department of Organic and Medicinal Chemistry, Wrocław University of Science and Technology, Wybrzeże Wyspianskiego 27, 50-370, Wrocław, Poland.
³ Department of Physical and Quantum Chemistry, Wrocław University of Science and Technology, Wybrzeże Wyspianskiego 27, 50-370, Wrocław, Poland.
⁴ Virogenetics Laboratory of Virology, Małopolska Centre of Biotechnology, Jagiellonian University, Gronostajowa 7a, 30-387, Kraków, Poland.
⁵ Laboratory of Proteolysis and Post-translational Modification of Proteins, Małopolska Centre of Biotechnology, Jagiellonian University, Gronostajowa 7a, 30-387, Kraków, Poland.
⁶ Faculty of Chemistry, Jagiellonian University, Gronostajowa 2, 30-387, Kraków, Poland.
⁷ Univ. Bordeaux, Inserm U1212, CNRS UMR 5320, ARNA Laboratory, IECB, 33706, Pessac, France.
⁸ Department of Physical and Quantum Chemistry, Wrocław University of Science and Technology, Wybrzeże Wyspianskiego 27, 50-370, Wrocław, Poland. Electronic address: [email protected].
⁹ Department of Organic and Medicinal Chemistry, Wrocław University of Science and Technology, Wybrzeże Wyspianskiego 27, 50-370, Wrocław, Poland. Electronic address: [email protected].
¹⁰ Virogenetics Laboratory of Virology, Małopolska Centre of Biotechnology, Jagiellonian University, Gronostajowa 7a, 30-387, Kraków, Poland. Electronic address: [email protected].

PMID: 37054954
DOI: 10.1016/j.antiviral.2023.105604

Abstract

Herpes simplex virus type 1 (HSV-1) is a widespread human pathogen known to cause infections of diverse severity, ranging from mild ulceration of mucosal and dermal tissues to life-threatening viral encephalitis. In most cases, standard treatment with acyclovir is sufficient to manage the disease progression. However, the emergence of ACV-resistant strains drives the need for new therapeutics and molecular targets. HSV-1 VP24 is a protease indispensable for the assembly of mature virions and, as such, constitutes an interesting target for the therapy. In this study, we present novel compounds, KI207M and EWDI/39/55BF, that block the activity of VP24 protease and consequently inhibit HSV-1 infection in vitro and in vivo. The inhibitors were shown to prevent the egress of viral capsids from the cell nucleus and suppress the cell-to-cell spread of the infection. They were also proven effective against ACV-resistant HSV-1 strains. Considering their low toxicity and high antiviral potency, the novel VP24 inhibitors could provide an alternative for treating ACV-resistant infections or a drug to be used in combined, highly effective therapy.

Keywords: Antivirals; Cold sores; HSV-1; Herpes simplex; Protease; Therapy; Treatment.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acyclovir / pharmacology
Antiviral Agents / therapeutic use
Drug Resistance, Viral
Herpes Simplex* / drug therapy
Herpesvirus 1, Human*
Humans
Peptide Hydrolases

Substances

Peptide Hydrolases
Antiviral Agents
Acyclovir